Genetic Alterations in Heparan Sulfate Disrupt MCP‐1 Binding in the Injured Vessel

Abstract

Chemokine binding and distribution require heparan sulfate proteoglycans as co-receptors and are influenced by sulfation of the heparan sulfate (HS) side chains. The objective was to test the hypothesis that alterations in HS sulfation would disrupt chemokine binding and influence vascular remodeling in the setting of injury. We previously demonstrated that injury induced a 20 fold increase in mRNA encoding N-deactylase/N-sulfotransferase-1 (NDST1), an enzyme catalyzing the initial N-sulfation of HS side chains. We established a genetic mouse model in which NDST1 was deleted in smooth muscle (smMHCcre/NDST1flox). This model exhibited a significant decrease in NDST1 mRNA and in the ratio of mono-N-sulfated/unsulfated disaccharides (control 0.45±0.02 vs smMHCcre/NDST1flox 0.22±0.02, n=4, p<0.05). The macrovasculature develops normally in these mice. However, vascular injury induces a marked disruption in the gradient distribution of monocyte chemoattractant protein-1, a chemokine requiring HS and known to play a critical role in vascular remodeling. Similar results were observed in a second genetic model harboring a single allele deletion of NDST1. In sum, these findings provide early genetic evidence that HS sulfation is critical for chemokine distribution in the vessel in response to injury. This study is funded by American Heart Association.